1. Academic Validation
  2. Autophagic HuR mRNA degradation induces survivin and MCL1 downregulation in YM155-treated human leukemia cells

Autophagic HuR mRNA degradation induces survivin and MCL1 downregulation in YM155-treated human leukemia cells

  • Toxicol Appl Pharmacol. 2020 Jan 15;387:114857. doi: 10.1016/j.taap.2019.114857.
Jing-Ting Chiou 1 Yuan-Chin Lee 1 Chia-Hui Huang 1 Yi-Jun Shi 1 Liang-Jun Wang 1 Long-Sen Chang 2
Affiliations

Affiliations

  • 1 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
  • 2 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: lschang@mail.nsysu.edu.tw.
Abstract

The aim of this study was to investigate the mechanism of YM155 cytotoxicity in human chronic myeloid leukemia (CML) cells. YM155-induced Apoptosis of human CML K562 cells was characterized by ROS-mediated p38 MAPK activation, mitochondrial depolarization, and Survivin and MCL1 downregulation. Moreover, YM155-induced Autophagy caused degradation of HuR mRNA and downregulation of HuR protein expression, which resulted in destabilized Survivin and MCL1 mRNA. Interestingly, Survivin and MCL1 suppression contributed to autophagy-mediated HuR mRNA destabilization in YM155-treated cells. Pretreatment with inhibitors of p38 MAPK or Autophagy alleviated YM155-induced Autophagy and Apoptosis in K562 cells, as well as YM155-induced downregulation of HuR, Survivin, and MCL1. Ectopic overexpression of HuR, Survivin, or MCL1 attenuated the cytotoxic effect of YM155 on K562 cells. Conversely, YM155 sensitized K562 cells to ABT-199 (a BCL2 inhibitor), and circumvented K562 cell resistance to ABT-199 because of its inhibitory effect on Survivin and MCL1 expression. Overall, our data indicate that YM155-induced Apoptosis is mediated by inducing autophagic HuR mRNA degradation, and reveal the pathway responsible for YM155-induced downregulation of Survivin and MCL1 in K562 cells. Our findings also indicate a similar pathway underlying YM155-induced death in human CML MEG-01 cells.

Keywords

Chronic myeloid leukemia; HuR; MCL1; Survivin; YM155.

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